Production of a 3-(lower acyl) amino-3-carbalkoxy-2-piperidones



Patented Feb. 7, 195% (LOWER. ACYL) AMINO.- 3-oAneALKoxY-amriinrnoms PRODUCTION OF A 3- Noel F. Albcrtson,

Archer, Albany, signrnents, to

York, N. Y., a. corporat East Greenbush, and Sydney N; Y., assignors, by mesne as,- WinthropaStearns 1-119 N ion. of Delaware No Drawing. Application June 16, 1945, Serial No. 599,970

3 Claims. (01. cam-294) This invention relates to a process for the preparation of certain diaminocarboxylic acids and to the intermediates utilized in said process.

The principal object of this invention is the provision of a method for obtaining ornithine and substitution products thereof on a large scale and in high yield.

Although several methods for synthesizing ornithine are available in the literature, none of these gives a good yield of the desired amino acid and most of them require numerous steps. We have now discovered that ornithine and related amino acids can be readily synthesized in high yield by a three-step process which is adaptable to large-scale manipulation.

In general, our process comprises: condensing an acrylonitrile with a lower alkyl (lower acylamino)-malonate; catalytically hydrogenating the condensation product, whereby a piperidone is obtained; and hydrolyzing and decarboxylating the piperidone to yield ornithine or substitution product thereof.

We have found that acrylonitriles can be reacted in the manner of the Michael condensation [J. Org. Chem., 3, 570 (1939)] with lower alkyl (lower acylamino)-malonates, -cyanoacetates and -acetoacetates in accordance with the equation:

wherein X is cyano, acetyl, or carbalkoxyl. It is-to. be understood that in this illustrative equa' tion, and in those which follow, the unattached valences are satisfied by groups unreactive under conditions of the Michael reaction. The condensation is effected by a catalytic base, and for this purpose we have found that approximately from 1 to 20 mole per cent, preferably about 4 mole per cent, of alkali metal alkoxide, such as sodium ethoxide, is most suitable. Under ordinary conditions, secondary amines such as piperidine and diethylamine have been found to be too weak to be efiective.

The use of as much as 100 mole per cent, 1. e. an equivalent portion, of alkali metal alkoxide leads to the formation of undesired products and thus is to be avoided. Provided that mild con densation conditions are employed, alkali metals or alkali metal amides or other like strong bases can be employed in place of the alkali metal aligoxide. While we have .found it to be convenient to. use a lower anhydrous alcohol such as anhydrous ethyl alcohol, inert diluents such as benzene, or ether can be. employed; alternatively the diluent may be omitted entirely.

We have found that certain of the condensation products obtained in the above ,fashiomviz. wherein X is carbalkoxyl, are useful as intermediates adapted to a new synthesis of ornithine and related amino acids. These condensation products chemically can be, designated-aslower alkyl (beta-cyanoalkyl-)- (lower :acyl) aminomalohates. Since the unsaturated. nitrilecomponent employed in the Michael condensation can beany having no other groupings reactive under the conditions of the condensation, it will be appreciated that acrylonitriles substituted by groups such as methyl, ethyl, phenyl, anisyl, and soon fall within the purviewoftheinvention, and accordingly, the term (beta-cyanmalkyD-is tobe understood to include alkyl groups substituted. in corresponding fashion. These condensation products, when hydrogenated inthe presencelof a metal catalyst, for example Raney nickel, platinum, or palladium, areconverted. to piperidone derivatives accordingto the equation:

0 0 O-(lower alkyl) The product is obtained in the form of a salt with the acid used in the hydrolysis. The hy- 3 drolysis and decomposition step can conveniently be efiected by boiling with moderately strong aqueous mineral acid, such as concentrated hydrochloric acid or approximately 20% sulfuric acid.

Hydrolysis of the piperidones with concentrated alkali solution produces alkali metal salts of (gamma-aminopropyl) (lower acyl) aminomalonic acids. These acids lose carbon dioxide when heated, thus forming 3-acylamino-2-piperidones. The (gamma-aminopropyl) (lower acyl) aminomalonic acids can be condensed with cyanamide, dicyandiamide, an isothiuronium salt, or a guanidine salt to yield delta-guanido derivatives which can be hydrolyzed to arginine or substitution products thereof.

The terms lower alkyl and lower acyl as used in the above discussion and in the subjoined claims refer to those aliphatic groups of lower molecular weight having about five carbon atoms or less, so that the respective hydroxyl derivatives, alcohols or acids respectively, are wholly or in substantial degree water-soluble. This requirement is of spractical significance because the by-products of the reactions are then readily removed.

Our invention is illustrated by the following example, but is not limited thereto.

Examplewater. 'The white solid which precipitates is collected on a filter. This product, which is ethyl (beta cyanoethyl)acetamidomalonate, weighs 253-257 g. and melts at 92-94 C.

127 g. of ethyl (beta-cyanoethyl)acetamidomalonate is dissolved in 400 ml. of ethyl alcohol and is treated at 68 C. with hydrogen under a pressure of 600 lbs. per sq. in. The reduction is complete after one The catalyst is removed from the reaction mixture by filtration and the filtrate is concentrated in vacuo to remove most of the ethyl alcohol. The residue is cooled and the solid is collected on a filter and is washed successively with very small portions of cold ethyl alcohol and ethyl ether. The white, crystalline product, which is ,3 acetamido-3carbeth0Xy-2-piperidone, weighs 96 g. and melts at 136-1385 0.

22.8 g. of 3-acetamido-3-carbethoxy-2-piperi- .done is refluxed for four hours with 100 ml. of

concentrated hydrochloric acid and the reaction mixture is then evaporated to dryness. The residue is dissolved in 60 ml. of ethyl alcohol and about 14 ml. of concentrated ammonium hydroxide is added to neutralize the solution, which is cooled in ice for one hour. The solid is collected on a filter and washed with ethyl alcohol. To free it of ammonium chloride, the residue is suspended in 150 ml. of boiling 95% ethyl alcohol and the suspension is filtered. The residue, which The filtrate is concentrated in and one-half hours.

4 is dl-ornithine hydrochloride, weighs 16.4 g. and melts at 225 C. with decomposition. If the free amino acid, ornithine, is desired it can readily be obtained from the above hydrochloride by known means.

If in the above example methacrylonitrile is substituted for the acrylonitrile, the condensation with ethyl acetamidomalonate produces ethyl (beta cyanopropyl)acetamidomalonate, which on hydrogenation yields 3-acetamido-3- carbethoxy-5-methyl-2-piperidone, and the latter on hydrolysis and decomposition yields the hydrochloride of alpha, delta-diamino-gammamethylvaleric acid.

The lower alkyl (beta cyanoalkyl) (lower acyDaminomalonates disclosed in this applica REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS OTHER REFERENCES Traube et al., Beilstein (4 ed. 1922), vol 4, p. 501.

Bergman et al., Zeit fur physiol. Chem., vol. 159, pp. 179-189 (1926).

Montmollin et al., Helv. Chim Acta, Vol. 12,

Fischer et al., Beilstein (4 ed. 1935), vol. 22, p. 515.

Karrer, Organic Chem. (1938 Nordeman), p. 248.

Sidgewich, Organic Chemistry of Nitrogen, Taylor and Baker, Oxford, 1942 reprint, p. 120.

Koelsch, Jour. Amer. Chem. Soc., vol. 65, pp. 2093-2095 (1943).

Koelsch, Jour. Amer. Chem. Soc., vol. 65, pp. 24582460 (1943).

Ser. No. 374,864, Wiest (A. P. 0.), pub. June 15. 1943. 

1. THE PROCESS WHICH COMPRISES CATALYTICALLY HYDROGENATING A LOWER ALKYL (BETA-CYANOALKYL)(LOWER ACYL)-AMINOMALONATE IN THE PRESENCE OF A METAL CATALYST, THEREBY FORMING A 2-PIPERIDONE DERIVATIVE. 